Tuesday, March 27, 2012

Heparin induced thrombocytopenia

Drug-induced thrombocytopenia due to heparin differs from
that seen with other drugs in two major ways.

(1) The thrombocytopenia is not usually severe, with
nadir counts rarely <20,000/L.

(2) Heparin-induced thrombocytopenia (HIT) is not
associated with bleeding and, in fact, markedly increases the risk of
thrombosis.

Pathology:

HIT results from antibody formation to a complex of the
platelet-specific protein platelet factor 4 (PF4) and heparin. The
antiheparin/PF4 antibody can activate platelets through the FcRIIa receptor and
also activate monocytes and endothelial cells. Many patients exposed to heparin
develop antibodies to heparin/PF4, but do not appear to have adverse
consequences.

1) A fraction of those who develop antibodies will
develop HIT, and a portion of those (up to 50%) will develop thrombosis (HITT).

2) HIT can occur after exposure to low-molecular-weight
heparin (LMWH) as well as unfractionated heparin (UFH), although it is about 10
times more common with the latter. Occurrence is about 1-4 % of individuals
treated with UFH.

3) Most patients (0.5%) develop HIT after exposure to heparin
for 5–14 days. It occurs before 5 days (at times even hours) in those who were
exposed to heparin in the prior few weeks or months (<100 days) and have
circulating antiheparin/PF4 antibodies. Rarely, thrombocytopenia and thrombosis
begin several days after all heparin has been stopped (termed delayed-onset
HIT). The incidence of heparin-induced thrombocytopenia appears particularly
high after orthopedic surgery and is higher among surgical patients than
medical patients. Heparin-induced thrombocytopenia is uncommon among pediatric
patients and obstetrical patients and patients receiving long-term
hemodialysis.

The 4 T's have been recommended to be used in a
diagnostic algorithm for HIT:

1) Thrombocytopenia (unexplained fall in the platelet
count by 50% or more),

2) Timing of platelet count drop (5-15 days from exposure
to heparin),

3) Thrombosis newly formed even if patient is receiving
heparin therapy and other sequelae such as localized skin reactions (at sites
of subcutaneous injections), and

4) Other causes of thrombocytopenia not evident.

Category

2 points

1 point

0 points

Thrombocytopenia

Platelet count fall
> 50% and platelet nadir ≥ 20 × 109 L−1

Platelet count fall
30%–50% or platelet nadir 10–19 × 109 L−1

Platelet count fall
< 30% or platelet nadir < 10 × 109 L−1

Timing of platelet
count fall

Clear onset between
days 5 and 10 or platelet fall ≤ 1 day (prior heparin exposure
within 30 days)

Consistent with days
5–10 fall, but not clear (e.g. missing platelet counts) or onset after day 10
or fall ≤ 1 day (prior heparin exposure 30–100 days ago)

In the initial validation study (referenced above) the
following screening cut-offs for total HEP Score were modeled for sensitivity
and specificity:

> 2 = positive for HIT

< 2 = negative for HIT

(Sensitivity 1.00 [0.56 – 1.00],

Specificity 0.60 [0.45 - 0.75])

> 5 = positive for HIT

< 5 = negative for HIT

(Sensitivity 0.86 [0.42 – 0.99],

Specificity 0.88 [0.74-0.96])

Laboratory
Testing for HIT:

HIT (anti-heparin/PF4) antibodies can be detected using
two types of assays. The most widely available is an enzyme-linked immunoassay
(ELISA) with PF4/polyanion complex as the antigen. Since many patients develop
antibodies but do not develop clinical HIT, the test has a low specificity for
the diagnosis of HIT. This is especially true in patients who have undergone
cardiopulmonary bypass surgery, where approximately 50% of patients develop
these antibodies postoperatively. IgG-specific ELISAs increase specificity but
may decrease sensitivity.

The other assay is a platelet activation assay, which
measures the ability of the patient's serum to activate platelets in the
presence of heparin in a concentration-dependent manner. This test has lower
sensitivity but higher specificity than the ELISA. However, HIT remains a
clinical diagnosis.

Treatment:

Early recognition is key in treatment of HIT.

1) Discontinue all forms of heparin. HIT antibodies
cross-react with LMWH, and these preparations should not be used in the treatment
of HIT. Patients requiring anticoagulation should be switched from heparin to
an alternative anticoagulant. The direct thrombin inhibitors (DTIs) argatroban
and lepirudin are effective in HITT. Argatroban is given as continuous infusion
of 0.5-1.2 µg/kg/min
and titrated with aPTT=1.5-3 x baseline value. Lepirudin is given as a bolus of
0.4 mg/kg IV followed by continuous infusion of 0.15 mg/kg/h, titrated to
1.5-2.5 x baseline value for aPTT. The
aPTT should be checked 2 hours after initiating the infusion and repeated after
each dose adjustment. There is less bleeding tendencies with argatroban.

2) Thrombosis is a common complication of HIT, even after
heparin discontinuation, and can occur in both the venous and arterial systems
(30 x more risk to develop a thrombus when compared to control). Patients with
higher anti-heparin/PF4 antibody titers have a higher risk of thrombosis. In
patients diagnosed with HIT, imaging studies to evaluate the patient for
thrombosis (at least lower extremity duplex Dopplers) are recommended.

3) Follow platelet counts daily until recovery occurs.

4) Because of the high rate of thrombosis (mostly venous)
in patients with HIT, anticoagulation should be strongly considered, even in
the absence of thrombosis. In patients with thrombosis, patients can be
transitioned to warfarin, with treatment usually for 3–6 months. In patients
without thrombosis, the duration of anticoagulation needed is undefined. An
increased risk of thrombosis is present for at least 1 month after diagnosis;
however, most thromboses occur early, and whether thrombosis occurs later if the
patient is initially anticoagulated is unknown. Options include continuing
anticoagulation until a few days after platelet recovery or for one month.

Introduction of warfarin alone in the setting of HIT or
HITT may precipitate thrombosis, particularly venous gangrene and skin necrosis,
presumably due to clotting activation and severely reduced levels of proteins C
and S. Warfarin therapy, if started, should be overlapped with a DTI or fonda
parinux, and started after resolution of the thrombocytopenia (platelet count
>100000/mm3) and lessening of the prothrombotic state.

Always stop infusion of argatroban temporarily for around
2 hours when taking sample for INR measurement and subsequent exposure to
heparin should be avoided in all patients with a prior history of HIT.

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